Inflammatory diseases, such as arthritis or related arthritic conditions (e.g., ankylosing spondylitis, osteoarthritis and rheumatoid arthritis), Behcet's disease, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), psoriasis, atopic dermatitis and contact dermatitis are prevalent and problematic ailments. TNF-α plays a central role in the inflammatory response and the administration of their antagonists block chronic and acute responses in animal models of inflammatory disease. Enhanced or unregulated TNF-α production has been implicated in a number of diseases, for example ankylosing spondylitis, Behcet's disease, rheumatoid arthritis, Crohn's disease, and ulcerative colitis.
Phosphodiesterase type 4 (PDE4) belongs to a family of isoenzymes referred to as cyclic nucleotide phosphodiesterases (PDE). It is believed that the primary cellular mechanism for the inactivation of cAMP is the breakdown of adenosine 3′,5′-cyclic monophosphate (cAMP) by PDE. Inhibition of PDE4 has been shown to be particularly effective in the inhibition of inflammatory mediator releases.
No treatment for a diagnosed disease is 100% effective in all patient populations having the disease. For example, in the largest study trial, etanercept produced a response rate of 57% compared with 22% for placebo after 24 weeks (response was determined via the validated ASAS 20 response criteria developed by the Assessments in Ankylosing Spondylitis [ASAS] Working Group). See McCormack et al., BioDrugs: clinical immunotherapeutics, biopharmaceuticals and gene therapy 18 (3): 199-205 (2003). Accordingly, there is still a significant need for accurate and sensitive methods of identifying patients with various inflammatory diseases or disorders that are likely to be responsive to a treatment.